Taste-masked pharmaceutical compositions

ABSTRACT

There is provided a method for preparing an orally disintegrating tablet (ODT) composition comprising microparticles of one or more taste-masked active pharmaceutical ingredient(s), rapidly-dispersing microgranules, and other optional, pharmaceutically acceptable excipients wherein the ODT disintegrates on contact with saliva in the buccal cavity in about 60 seconds forming a smooth, easy-to-swallow suspension. Furthermore, the microparticles (crystals, granules, beads or pellets containing the active) applied with a taste-masking membrane comprising a combination of water-insoluble and gastrosoluble polymers release not less than about 60% of the dose is in the stomach in about 30 minutes, thus maximizing the probability of achieving bioequivalence to the reference IR product having rapid onset of action (short Tmax). A process for preparing such compositions for oral administration using conventional fluid-bed equipment and rotary tablet press is also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/248,596, filed Oct. 12, 2005, which claims the benefit of U.S.Provisional Application No. 60/617,737, filed Oct. 12, 2004, each ofwhich is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to an orally disintegrating tablet (ODT)composition comprising taste-masked microparticles of one or more activepharmaceutical ingredients suitable for oral administration for thetreatment of diseases and rapidly-dispersing microgranules comprising adisintegrant and a sugar alcohol or a saccharide, or a mixture thereof,each of which have an average particle diameter of not more than about30 μm. The multi-particulate ODT composition comprisingrapidly-dispersing microgranules and drug-containing core particles(crystals or granules, beads or pellets of one or more activepharmaceutical ingredients) coated with a taste-masking membranecomprising a blend of a water-insoluble polymer with a gastrosolublepolymer, rapidly disintegrates on contact with saliva when placed in theoral cavity forming a smooth, easy-to-swallow suspension containingcoated drug particles exhibiting acceptable taste-masking and providesrapid, substantially-complete release of the dose on entry into thestomach, thereby enhancing the probability of achieving bioequivalenceto the reference immediate release (IR) product. The inventionadditionally provides a method of manufacturing orally disintegratingtablets comprising rapidly-dispersing microgranules and acceptablytaste-masked microparticles, each population having an average particlesize of not more than about 400 μm, preferably not more than about 300μm, to provide a smooth mouthfeel leaving no aftertaste (non-gritty ornon-chalky taste) after swallowing the suspension.

BACKGROUND OF THE INVENTION

There are two types of most widely used dosage forms for oraladministration: tablets and capsules. However, such dosage forms haveseveral disadvantages. For example, it is estimated that 50% of thepopulation have problems swallowing tablets (see Seager in Journal ofPharmacol and Pharm. 50, pages 375-382, 1998); especially it is hard foraged persons to swallow tablets or capsules or to medicate children whoare unable or unwilling to swallow tablets or capsules. This leads topoor compliance, even non-compliance, with the treatment and thus has anegative impact on the efficacy of the treatment. Many therapeuticagents are bitter. The bitter taste precludes the medication from beingeasily sprinkled onto food such as applesauce, a commonly used method ofadministering medications to children. The conventional capsule ortablet dosage form is also inconvenient for the “people on the move” whooften do not have access to drinking water or fluids. Chewable tabletscomprising taste-masked particles capable of being chewed withoutexperiencing a bitter taste were introduced not too long ago, and thesetablets became popular with children.

The bitter drug-containing cores incorporated into chewable tablets havethick coatings of mostly water-insoluble polymers such as ethylcelluloseto resist fracture during tablet compression and/or during chewing andconcomitant leakage of the bitter active. Consequently, substantiallycomplete release of the drug from such chewable tablets in thegastrointestinal tract may take 2 hours or longer. More recently, orallydisintegrating tablet (ODT) dosage forms have been introduced, whichrapidly dissolve or disintegrate in the buccal cavity and hence can betaken without water. Such medicines are convenient for all, agedpersons, children or “people on the move”.

An ideal orally disintegrating tablet formulation comprisingrapidly-dispersing granules and drug-particles (crystals, pellets,granules, or beads containing the drug) with a taste-masking membrane(if required) should rapidly disintegrate on contact with saliva in theoral cavity forming a smooth, easy-to-swallow suspension containingtaste-masked drug particles having an average particle diameter of notmore than about 400 μm to provide 8 smooth mouthfeel leaving noaftertaste (i.e., little or minimal drug release with a non-gritty ornon-chalky taste) until swallowed, and should provide rapid,substantially-complete release upon arrival in the stomach in order tobe bioequivalent to the immediate-release reference-listed-drug product.

As indicated earlier, most of the actives in the marketed products arebitter to a varying degree. Typically, to eliminate/minimizedrug-release in the oral cavity, the bitter drug substance wastaste-masked in the prior art by providing a thick polymer-membranearound the drug particle typically by microencapsulation (coacervationby phase separation) or fluid-bed coating for preparing immediaterelease dosage forms (chewable tablets, sprinkles, sachets,suspensions). However, coating with water-insoluble polymers such asethylcellulose (EC), cellulose acetate (CA), cellulose acetatephthalate, polyvinyl acetate, Eudragit® RS, RL, L, S and NE30D polymers,results in slower dissolution profiles and not-too-infrequently resultsin imparting sustained-release properties.

Several marketed products, which are typically conventional oreffervescent based immediate-release dosage forms, have a T_(max) ofless than an hour and rapid-onset of action. An undesirable consequenceof taste-masking in general is the slower release of the drug in thegastrointestinal tract. Eudragit® E (EPO or E100), a copolymerconsisting of dimethylaminoethyl methacrylate and neutral methacrylicacid esters with a weight-average molecular weight of 150,000 and apK_(a) of 6.3, is readily soluble under acidic conditions afterprotonation of the substituted amino groups. In a neutral or alkalineenvironment, the polymer swells and the coating film becomeswater-permeable and the polymer film slowly erodes and dissolves. Thesaliva is typically in the pH range of 6.7 to 7.4. Hence, it is likelythat one achieves effective taste-masking in the oral cavity for alimited time if the drug core is coated with Eudragit E100/EPO alone orin combination with a water-soluble agent.

From a pharmaceutical and a practical point of view, the inventors ofthe present invention have examined various methods of taste-maskingbitter active pharmaceutical ingredients suitable for incorporation intoorally disintegrating tablets having the property of rapidlydisintegrating in the buccal cavity and leaving no aftertaste (goodcreamy mouthfeel) and additionally providing rapid,substantially-complete release of the dose in the stomach, therebyenhancing the probability of achieving bioequivalence to the referenceproduct with a rapid-onset of action. The method of producingtaste-masked microparticles (mean particle size of about 100-400 μm) inaccordance with the present invention comprising one or more bitteractive pharmaceutical ingredients) includes membrane-coating ofdrug-containing core particles (crystals, microgranules, drug-layered orextruded/spheronized-beads) with a mixture of a water-insoluble polymer,such as ethylcellulose or polyvinyl acetate, and a gastrosolublepolymer, such as Eudragit E100, at a ratio of about 50/50 to 95/5 for aweight gain of not less than about 5% and not more than about 50% byweight, based on total weight of the coated particle. Furthermore, themicroparticles prepared in accordance with the present invention can beproduced to exhibit the specified criteria (viz., desired particle sizedistribution, little or minimal release of the bitter active in themouth (hence no aftertaste), and rapid-release of the dose from thetaste-masked microparticles upon entry into the stomach) to be suitablefor incorporation into orally disintegrating tablets. In accordance withparticular embodiments, both the water-insoluble polymer and thegastrosoluble polymer are dissolved in the same solvent system andsprayed on to drug-containing particles in a fluid-bed coater. Hence,one can expect to find, without going into the mechanism, a random buthomogeneous disposition of individual polymer molecules in the membrane.As the gastric fluid rapidly penetrates into the bead-core, one canexpect to find microchannels being formed ensuring rapid release of theactive.

The taste-masking effectiveness is measured by the percent of the dosereleased in a simulated saliva fluid at a pH of 6.7-7.4. The smaller thepercent release, the more effective the taste-masking. A pharmaceuticalcomposition with a release of not more than 10% of the dose in about 3minutes in a simulated saliva fluid (the longest anticipated residencetime for taste-masked microparticles in the mouth) is consideredacceptably taste-masked. On the other hand, the drug release on oraladministration is evaluated by measuring the percent of the dosereleased in an acidic pH of about 1.2. The faster the release of thedrug from the taste-masked microparticles in the stomach, the higher theprobability of being bioequivalent to the reference product. A releaseof not less than about 60% of the dose in about 30 minutes in the acidicbuffer is considered acceptable for achieving bioequivalence to thereference product.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions and methodsfor making taste-masked microparticles and orally disintegratingtablets. In accordance with particular embodiments, the compositions mayprovide effective taste-masking, smooth mouthfeel (no aftertaste) andrapid/complete release upon reaching the stomach, thereby enhancing theprobability of achieving bioequivalence to the reference product.

The multi-particulate compositions comprise taste-masked core particles(crystals or granules, beads or pellets comprising one or morebitter-tasting active pharmaceutical ingredients) produced by coatingwith a mixture of a water-insoluble polymer and a gastrosoluble polymer.The taste-masked composition prepared in accordance with the presentinvention rapidly releases the drug, i.e., not less than about 60% ofthe dose released in 30 minutes when tested for dissolution using UnitedStates Pharmacopoeia Apparatus 1 (baskets @ 100 rpm) or 2 (paddles @ 50rpm) in 900 mL of 0.1N HCl. Another embodiment of the invention relatesto a pharmaceutical composition in the form of an orally disintegratingtablet comprising (i) rapidly-dispersing microgranules comprising (a) adisintegrant and (b) a sugar alcohol or a saccharide whose averageparticle size is not more than about 30 μm, (ii) microparticles of oneor more bitter-tasting active pharmaceutical ingredients taste-maskedwith a polymer membrane comprising a blend of a water-insoluble polymerand a gastrosoluble polymer and (iii) optionally other pharmaceuticallyacceptable excipients. In accordance with particular embodiments, theseorally disintegrating tablets have the properties of disintegrating oncontact with saliva in the buccal cavity in about 60 seconds forming asmooth easy-to-swallow suspension with no aftertaste (good creamymouthfeel) and rapidly releasing the dose on entry into the stomach,thus enhancing the probability of being bioequivalent to the referenceproduct.

In accordance with one aspect of the invention, a taste-maskedmultiparticulate pharmaceutical composition comprising:

(a) a drug-containing core particle (crystal, granule, pellet, bead andthe like);

(b) a taste-masking membrane on said drug-containing core particlecomprising a combination of a water-insoluble polymer and agastrosoluble polymer at a ratio ranging from about 95/5 to about 50/50having a thickness of from about 5% to about 50% based on the weight ofthe coated particle and an average particle size of not more than about400 μm is disclosed.

In accordance with certain embodiments, the composition exhibitsacceptable taste-masking when the composition is placed in the oralcavity for 3 minutes, preferably for 2 minutes and more preferably for60 seconds, most preferably until it is swallowed leaving little or noaftertaste (i.e., experiencing no gritty or chalky taste) and thecomposition provides rapid, substantially-complete release of the doseupon entry into the stomach, i.e., releases not less than 60% of thedose in 30 min when tested for dissolution using United StatesPharmacopoeia Apparatus 1 (Baskets@ 100 rpm in 900 mL of pH 1.2 buffer).

A taste-masked multiparticulate pharmaceutical composition in the ODT(orally disintegrating tablet) form, which disintegrates on contact withsaliva in the buccal cavity in about 60 seconds forming a smootheasy-to-swallow suspension (no gritty or chalky aftertaste) is alsodisclosed. The ODT may comprise the drug-containing core particle(crystal, granule, pellet, bead and the like), with a taste-maskingmembrane on the drug-containing core particle. The taste-maskingmembrane may comprise a water-insoluble polymer and a gastrosolublepolymer at a ratio ranging from about 95/5 to about 50/50 having athickness of from about 5% to about 50% based on the weight of thecoated microparticle with an average particle size of not more thanabout 400 μm, or in some embodiments not more than 300 μm. The ODT mayalso include a rapidly-dispersing microgranule with an average particlesize of not more than about 300 μm, or in some embodiments not more than200 μm, comprising a disintegrant and a sugar alcohol or a saccharide ora combination thereof, each having an average particle diameter of notmore than about 30 μm, and optionally pharmaceutically acceptableexcipients typically used in ODT formulations, viz., flavors, asweetener, coloring agents, and a disintegrant.

The ODT in accordance with one embodiment exhibits the followingproperties:

-   -   1) disintegrates on contact with saliva in the oral cavity in        about 60 seconds forming a smooth, easy-to-swallow suspension        comprising taste-masked microparticles and    -   2) taste-masked microparticles provide rapid,        substantially-complete release of the dose upon entry into the        stomach.

The ODT may comprise taste-masked microparticles demonstrating effectivetaste-masking by releasing not more than 10% in about 3 minutes (thelongest typical residence time anticipated for the ODT in the buccalcavity) when dissolution tested in a simulated saliva fluid (pH 6.8)while releasing not less than 60% of the dose in about 30 minutes whendissolution tested in 0.1N HCl.

A method of manufacturing a taste-masked multi-particulate compositionwherein the dosage form comprises one or more active pharmaceuticalingredient(s) in sufficient quantities to be administered orally to apatient at prescribed dosing regimen to provide therapeutic efficacy isalso provided.

The taste-masked multiparticulate pharmaceutical composition may includeany pharmaceutically acceptable active ingredient requiringtaste-masking.

In accordance with particular embodiments, the method of preparing ataste-masked multi-particulate composition includes layering apharmaceutically acceptable drug from a polymeric binder solution ontoan inert particle selected from the group consisting of sugar spheresand cellulose spheres. Fluid bed or pan coating may be used to apply theactive and polymeric binder solution.

In accordance with certain embodiments, the drug-containing particle isa microgranule or an extruded/spheronized pellet comprising one or morepharmaceutically acceptable active ingredient(s), a polymeric binder,which imparts resilient characteristics to dried microgranules, ahydrophilic filler/diluent, and optionally a flavor, a sweetener and/ora disintegrant.

The microgranules of one or more active pharmaceutical ingredient(s) maybe prepared by a conventional high-shear or planetary granulationprocess or the pellets may be prepared by a conventionalgranulation-extrusion-spheronization process comprising an activepharmaceutical ingredient, a polymer binder and one or morefillers/diluents.

The water-insoluble polymer (preferably ethylcellulose with an averageviscosity of 10 cps) and the gastrosoluble polymer (preferably EudragitEPO) may be present at a weight ratio of from about 95/5 to 50/50, moreparticularly from about 85/15 to 65/35, and the membrane thicknessvarying from about 5% to 50%, more particularly from about 10% to 30%,by weight in accordance with particular embodiments.

In accordance with some particularly useful embodiments, thetaste-masked multiparticulate pharmaceutical composition includesrapidly-dispersing microgranules comprising a disintegrant, preferablycrospovidone, and a sugar alcohol (preferred mannitol) or a saccharide(lactose) or a combination thereof, each having an average particlediameter of not more than about 30 μm and a ratio of sugar alcoholand/or saccharide to disintegrant varying from about 90/10 to about99/1.

The rapidly-dispersing microgranules and taste-masked microparticles maybe present in the ratio of about 6/1 to 2/1, more particularly fromabout 4/1 to 3/1, to achieve a smooth mouthfeel in some embodiments ofthe taste-masked composition.

A method of manufacturing a taste-masked multi-particulate compositionof one or more active pharmaceutical ingredient(s) is also provided. Themethod may comprise the steps of:

-   -   a) preparing core particles of one or more active pharmaceutical        ingredient(s) as granules by a conventional granulation process,        as beads by drug-layering onto inert particles from a polymeric        binder solution in a fluid-bed equipment, or as microgranules or        as pellets by a conventional granulation of one or more active        pharmaceutical ingredient(s), one or more polymeric binders), a        hydrophilic filler/diluent, and optionally a flavor, a        sweetener, and/or a disintegrant or        granulation-extrusion-spheronization process; and    -   b) coating core particles by applying a membrane comprising a        mixture (at a ratio of 95/5 to 50/50) of water-insoluble        ethylcellulose and gastrosoluble Eudragit E100 dissolved in a        mixture of acetone and purified water, the membrane coating        comprising approximately from about 5% to about 50% based on the        total weight of the coated particles.

The composition may exhibit the following properties:

-   -   1) acceptable taste-masking when the composition is placed in        the oral cavity for 3 minutes, more particularly for 2 minutes        and in certain embodiments for 60 seconds, and in still other        embodiments, until it is swallowed leaving no aftertaste; and    -   2) rapid substantially complete release of the dose upon entry        into the stomach, i.e., releases not less than 60% of the dose        in 30 min when tested for dissolution using United States        Pharmacopoeia Apparatus 1 (Baskets @ 100 rpm) or Apparatus 2        (paddles @ 50 rpm in 900 mL of pH 1.2 buffer).

In a particular embodiment of the invention, the method comprises thesteps of:

-   -   a) preparing core particles (crystals with a particle size        distribution of 20-500 μm, more particularly from about 50-300        μm, beads, microgranules, pellets) of one or more active        pharmaceutical ingredient(s) as described above;    -   b) taste-masking core particles by applying a membrane        comprising a mixture of water-insoluble and gastrosoluble        polymers as described above, the membrane coating comprising        approximately from about 5% to about 50% based on the total        weight of the coated particles;    -   c) granulating a disintegrant such as crospovidone with a sugar        alcohol or a saccharide, or a combination thereof, each having        an average particle diameter of not more than 30 μm, with water        or an alcohol-water mixture in a conventional granulator and        drying in a fluid bed equipment to produce granules with an        average particle size not more than 400 μm (more particularly        not more than 300 μm);    -   d) blending taste-masked microparticles of step (b) with rapidly        disintegrating microgranules of step (c) and other optionally        acceptable ingredients such as a flavoring agent, a coloring        agent, a sweetener and additional disintegrant in sufficient        quantities; and    -   e) compressing into tablets using a conventional rotary tablet        press equipped with an external lubrication system to        pre-lubricate the dies and punches

The ODT may exhibit the following properties;

-   -   1) disintegrates on contact with the saliva in the oral cavity        forming a smooth, easy-to-swallow suspension comprising        taste-masked microparticles,    -   2) leaves no aftertaste after swallowed (no gritty or chalky        mouthfeel),    -   3) provides rapid, substantially-complete release of the dose        upon entry into the stomach; or    -   4) the ODT when tested for dissolution using United States        Pharmacopoeia Apparatus 1 (baskets @ 100 rpm) or Apparatus 2        (paddles @ 50 rpm) in 900 mL buffer releases not more than 10%        of the dose in about 3 minutes in a simulated saliva buffer at        pH 6.8 and not less than 60% of the dose in about 30 minutes in        an acidic buffer at pH 1.2.

These and other embodiments, advantages and features of the presentinvention become clear when detailed description and examples areprovided in subsequent sections.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the dissolution profiles in 0.1N HCl of taste-maskeddiphenhydramine citrate beads of Example 1;

FIG. 2 illustrates the dissolution profiles in 0.1N HCl of taste-maskeddiphenhydramine hydrochloride beads of Example 2 (comparative);

FIG. 3 illustrates the dissolution profiles in 0.1N HCl of taste-maskeddiphenhydramine hydrochloride beads of Example 4 (comparative);

FIG. 4 illustrates the dissolution profiles in 0.1N HCl of taste-maskeddiphenhydramine hydrochloride beads of Example 6.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

The term “drug”, “active” or “active pharmaceutical ingredient” as usedherein is meant to include the base, any pharmaceutically acceptablesalt, stereo-isomer and a mixture thereof. The term represents anytherapeutic agent indicated for oral administration. Examples include,but are not limited to, NSAID analgesic, histamine H₁-receptorantagonist, histamine H₂-receptor antagonist, 5-HT₁ receptor agonist,5-HT₃ receptor antagonist, antiepileptic drug, centrally actingadrenergic agonist, sleep-aid, leukotriene receptor antagonist, or drugfor the treatment of erectile dysfunction, requiring taste-masking.Specific examples of the therapeutic agent used in various embodimentsof this invention include one or more agents selected from the groupconsisting of sumatriptan, electriptan, cetirizine, zafirlukast,montelukast, famotidine, ranitidine, tiagabine, fexofenadine,tizanidine, ondansetron, granisetron, zolpidem, zaleplon, sildenafil,tadalafil, and the like.

An aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing drug containing core particles for taste-masking, viz.,beads by drug-layering onto inert sugar spheres in fluid-bed equipment.Examples of useful solvents include, but are not limited to acetone,ethanol, isopropanol, water or mixtures thereof. The type of filmforming binder that is used to bind the water-soluble drug to the inertsugar sphere is not critical but usually water-soluble, alcohol-solubleor acetone/water soluble binders are used. A binder such aspolyvinylpyrrolidone (FVP), polyethylene oxide, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), may be used atconcentrations of about 0.5 to 10 weight % based on the drug-layeredbeads. The drug substance may be present in this coating formulation insolution form or may be suspended at a solid content up to about 35%depending on the viscosity of the coating formulation.

Crystals of a bitter API with a desired particle size range (typicallyfrom about 20 μm to 500 μm, more particularly from about 50 μm to 300μm) can be taste-masked directly. Alternatively, microgranulescontaining milled or micronized drug particles can be produced bygranulating in a high-shear granulator the active and a suitablefiller/diluent (if required) with a polymeric binder, which impartsresilient characteristics to the dried microgranules to resist attritiondue to fluidization during fluid-bed coating for taste-masking. Therelative amounts of active, binder and optional filler/diluent may varyconsiderably depending on the particular active and the dosage form.Typically, microgranules prepared in accordance with this aspect of theinvention will contain from about 5% to about 95%, more particularlyfrom about 20% to about 90%, active and up to about 15% binder with anyoptional filler/diluent being present at from about 0% to 90%, moreparticularly from about 20% to 80%, by weight of the microgranules.

Useful polymeric binders include, without limitation,hydroxypropylcellulose (Klucel® LF from Aqualon), modified starch (e.g.,Starch 1551 and Starch 1500, commercially available from National Starchand Colorcon, respectively), Koilidon® VA 64, polyvinylacetate-vinylpyrrolidone) from BASF, and hydroxypropyl methylcellulosewith a viscosity of 100 cps or more (e.g., Methocel K100LV and MetoloseK400 commercially available from Dow Chemical and Shin Etsu Chemicals,respectively) alone or in combination with a widely used binder such asPVP (polyvinylpyrrolidone) and hydroxypropyl methylcellulose with aviscosity of 15 cps or less.

Examples of useful pharmaceutically acceptable fillers/diluents include,but are not limited to, mannitol, lactose, microcrystalline cellulose,potassium sulfate, calcium phosphate, modified starch and mixturesthereof.

The water-insoluble polymers suitable for taste-masking of bitter drugsby coating in fluid-bed equipment include, but are not limited to,ethylcellulose, cellulose acetate, cellulose acetate butyrate,methacrylate copolymers available under the trade name of Eudragit®(type RL, RS and NE30D). The gastrosoluble polymers include, but are notlimited to, maltrin, an aminoalkyl methacrylate copolymer availableunder the trade name of Eudragit® (type E100 or EPO), polyvinylacetaldiethylaminoacetate e.g., AEA® available from Sankyo Company Limited,Tokyo (Japan), and the like. The ratio of water-insoluble polymer togastrosoluble polymer for producing taste-masked particles may typicallyvary from about 95/5 to about 50/50, or in some embodiments from about85/15 to 65/35, at a thickness of from about 5% to about 50%, or in someembodiments from about 10% to about 30% by weight of the coated bead.

The membranes described herein may also include one or moreplasticizers. Representative examples of plasticizers that may be usedto plasticize the membranes include triacetin, tributyl citrate,triethyl citrate, acetyl tri-n-butyl citrate, polyethylene glycol,polypropylene glycol, diethyl phthalate, castor oil, dibutyl sebacate,acetylated monoglycerides and the like or mixtures thereof. Theplaslicizer may comprise typically about 10-30% or about 5-15% based onthe weight of dry polymer, depending on the use of polymer dispersionsor solutions.

The membranes described herein may also include one or more anti-tackyagents. Representative examples of anti-tacky agents that may be usedinclude, without limitation, talc and magnesium stearate.

The ODT composition described herein typically includerapidly-dispersing microgranules. One or more sugar alcohols and/orsaccharides and a disintegrant are granulated in a high-shear granulatorand dried in fluid bed equipment to produce rapidly-dispersingmicrogranules. Rapidly-dispersing microgranules typically will containsugar alcohol and/or saccharide and disintegrant at a ratio varying fromabout 90/10 to about 99/1, or in some embodiments from about 90/10 toabout 95/5 by weight (sugar alcohol and/or saccharide to disintegrant).The sugar alcohol may be selected from the group consisting of mannitol,sorbitol, xylitol, maltitol and the like while the saccharide may beselected from the group consisting of lactose, sucrose, maltose or as amixture of two or more, each of which is characterized by an averageparticle size of not more than about 30 μm. A disintegrant or aso-called super-disintegrant may be selected from the group consistingof crospovidone (crosslinked PVP), sodium starch glycolate, crosslinkedsodium carboxymethyl cellulose, and low substitutedhydroxypropylcellulose.

The ODT compositions may also include additional disintegrant separatefrom the rapidly dispersing microgranules. The additional disintegrantmay be present in the ODT formulation at up to about 10% based on thetablet weight.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that thedescription above as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Any modificationwithin the scope of the invention will be apparent to those skilled inthe art to which the invention pertains.

One method of producing taste-masked microparticles (mean particle sizeof about 100-400 μm) comprising one or more bitter active pharmaceuticalingredient(s) may include (i) preparing drug-containing particles(crystals with a desired particle size range (from about 20 μm to 500μm), microgranules, drug-layered or extruded/spheronized-beads) and (ii)membrane-coating of these drug-containing particles for taste-masking.The method of producing drug-layered beads in accordance with one aspectof the invention includes dissolving or suspending one or more activepharmaceutical ingredients in a polymeric binder solution and layeringonto inert particles such as sugar spheres or Celpherc (50-100 mesh or150-300 μm) using a fluid-bed coater equipped with a bottom-sprayWurster insert. Another embodiment of the method of producing resilientdrug-containing microgranules, which undergo little or minimal attritionduring membrane coating in fluid-bed equipment, includes granulating oneor more actives and a filler or diluent (if needed) with a polymericbinder solution in a high-shear granulator. Yet another embodiment ofthe method of producing drug-containing beads includes granulating theactive in a high-shear granulator as described above, followed byextrusion and spheronization of the wet mass usingextrusion-spheronization equipment.

The method of producing taste-masked microparticles (crystals,microgranules, drug-layered or extruded/spheronized-beads) in accordancewith one aspect of the invention includes fluid-bed coating with amixture of a water-insoluble polymer such as ethylcellulose or polyvinylacetate and a gastrosoluble polymer such as Eudragit E100 or AEA®(polyvinylacetal diethylaminoactate) at a ratio of about 50/50 to 95/5,more particularly at a ratio of about 50/50 to 80/20, and in accordancewith certain embodiments at a ratio of about 50/50 to 65/35, for aweight gain of from about 5% to about 50%, preferably from about 10% toabout 30%. One embodiment of the invention includes dissolvingwater-insoluble polymer (e.g., ethylcellulose) and gastrosoluble polymer(e.g., Eudragit EPO) in a 95/5 acetone/water with triethyl citrate (TEC)as the plasticizer (at about 10% of the weight of ethylcellulose) andwith talc as the anti-tacking agent at up to about 20% by weight of thegastrosoluble polymer, and coating the drug-cores (crystals,drug-layered beads, microgranules or pellets) in a fluid-bed coaterequipped with a bottom-spray Wurster insert.

The invention also provides a method of manufacturing in accordance withone aspect of the invention orally disintegrating tablets, produced bymixing taste-masked microparticles, rapidly-dispersing microgranules andoptionally one or more other excipients (for example: flavor, color,sweetener etc) and compressing the blend into orally disintegratingtablets. In accordance with certain aspects of the invention, the orallydisintegrating tablets rapidly disintegrate on contact with saliva inthe buccal cavity leaving little or no aftertaste (good creamymouthfeel) and provide rapid, substantially-complete release of the dosein the stomach, thereby enhancing the probability of achievingbioequivalence to the reference product.

Rapidly-dispersing microgranules may be produced in accordance with themethod of manufacturing rapidly-dispersing microgranules disclosed in aco-pending U.S. patent application Ser. No. 10/827,106, filed Apr. 19,2004 and co-pending U.S. patent application Ser. No. 11/213,266 filedAug. 26, 2005, the contents of which are hereby incorporated byreference. Rapidly dispersing microgranules with an average particlesize of about 125-300 μm, more particularly from about 150-200 μm,comprising a disintegrant (for example, Crospovidone XL-10) and a sugaralcohol or a saccharide or a mixture thereof (for example, D-mannitol)having an average particle diameter of not more than about 30 μm, may beproduced by granulating with only water in a high-shear granulator, wetmilling and drying in fluid bed equipment. The taste-maskedmicroparticles produced in accordance with the present invention andrapidly-dispersible microgranules may be blended with otherpharmaceutically acceptable ingredients and compressed into tablets. Thetablets rapidly disintegrate (e.g., typically in less than about 60seconds) in the buccal cavity with a smooth creamy mouth feel.

It is yet another embodiment of the invention to provide a method tomanufacture rapidly disintegrating tablets, which are characterized bythe property that the tablets are formed by compressing in a tabletpress equipped with an external lubricating system to pre-lubricate diesand punches and the tablet formulation otherwise being free oflubricant. The orally disintegrating tablets thus produced in accordancewith certain embodiments, exhibit sufficient hardness and sufficientlylow friability and are suitable for packaging in HOPE bottles andpush-through blister packs using conventional equipment for storage,transportation and commercial distribution.

The pharmaceutical taste-masked multiparticulate composition accordingto certain aspects of the present invention provides acceptabletaste-masking when placed in the mouth until swallowed (targetspecification: not more than about 10% of the dose released in about 3minutes when tested for dissolution in simulating saliva fluid at pH6.8). If the composition is in the ODT (orally disintegrating tablet)form, the tablet typically disintegrates on contact with the saliva inthe buccal cavity in about 60 seconds forming a smooth, easy-to swallowsuspension, comprising taste-masked microparticles with acceptableaftertaste. In accordance with particular embodiments of the invention,these taste-masked microparticles provide substantially-complete releaseof the dose on entry into the stomach (target specification: not lessthan about 60%, more particularly not less than about 75% and inaccordance with certain embodiments not less than about 80% of the dosereleased in about 30 minutes when tested for dissolution in simulatedgastric fluid or 0.1N HCl at pH 1.2).

In accordance with one aspect of the invention, a method ofmanufacturing taste-masked microparticle composition of one or morebitter-tasting therapeutic agent(s), which exhibits acceptabletaste-masking when placed in the oral cavity and provides arapid-release of the dose on entry into the stomach, comprises thefollowing steps:

a) preparing a drug containing core particle (crystal, bead, pellet orgranule) by (i) drug-layering on an inert particle (e.g., a 50-100 meshsugar sphere or a cellulose sphere (e.g., Celphere® CP-203 availablefrom Asahi Kasci Chemicals Corporation) from a solution/suspensioncomprising a polymeric binder and the drug in fluid bed equipment andoptionally coating with a seal-coat of Opadry® Clear, or (ii)granulating the drug and a filler/diluent such as lactose, mannitol ormacrocrystalline cellulose with a polymeric binder using a high-sheargranulator, or (iii) granulating as above and followed by extrusion andspheronization; and

b) coating the drug containing core particles with a solution of afunctional polymer blend comprising a water insoluble polymer and agastrosoluble polymer to produce effectively taste-masked microparticleswith a desired particle size distribution (an average particle size ofnot more than about 400 μm, more particularly not more than about 300μm).

In accordance with another aspect of the invention, the method ofmanufacturing orally disintegrating tablets, which disintegrate oncontact with saliva in the buccal cavity forming a smooth, easy-toswallow suspension with acceptable aftertaste, comprising taste-maskedmicroparticles, which rapidly release the dose on entry into thestomach, is provided. The method, in accordance with this aspect of theinvention, comprises the following steps:

a) preparing a drug containing core particle (crystal, bead, pellet orgranule) by (i) drug-layering on an inert particle (e.g., a 50-100 meshsugar sphere or cellulose sphere, such as Celphere® CP-203) from asolution/suspension comprising a polymeric binder and the drug in afluid bed coater and applying a seal-coat of Opadry® Clear, or (ii)granulating the drug and a diluent/filler such as lactose, mannitol ormicrocrystalline cellulose with a polymeric binder, or (iii) granulatingas above, followed by extrusion and spheronization;b) coating drug containing core particles with a solution of afunctional polymer blend comprising a water insoluble polymer and agastrosoluble polymer to produce effectively taste-masked microparticleswith a desired particle size distribution (an average particle size ofnot more than about 400 μm, more particularly not more than about 300μm);c) granulating a sugar alcohol or a saccharide, or a combinationthereof, each of which has an average particle diameter of not more thanabout 30 μm, with a disintegrant such as Crospovidone using water or analcohol-water mixture in a typical granulator and drying in fluid bedequipment to produce rapidly-dispersing microgranules with an averageparticle size not more than about 400 μm (typically with an averageparticle size of not more than about 300 μm);d) blending taste-masked microparticles of step (b) with rapidlydisintegrating microgranules of step (c) at a ratio of from about 1/6 to1/1 more particularly from about 1/4 to 1/2, and optionally otheracceptable ingredients such as a flavoring agent, a coloring agent, anda sweetener in sufficient quantities typically up to about 1%, moreparticularly about 0.5% and additional disintegrant up to about 5%, moreparticularly about 4% based on the tablet weight;e) compressing into tablets using a conventional rotary tablet pressequipped with an external lubrication system to pre-lubricate the diesand punches.

In Vitro Dissolution Testing:

The taste-masking property of the taste-masked microparticles and theorally disintegrating tablets in the mouth is evaluated by determiningthe percentage of drug-release (a release of not more than about 10% ofthe dose in about 3 minutes is considered acceptable) when tested fordissolution using USP Apparatus 1 (baskets @ 100 rpm) or Apparatus 2(paddles @ 50 rpm) in 900 mL of simulating saliva fluid at a pH of about6.8. Further, the rapid-release property in the stomach of thetaste-masked microparticles and the orally disintegrating tablets isevaluated by determining the percentage of drug-release (a release ofnot less than about 60% of the dose in about 30 minutes is typicallyconsidered acceptable) when tested for dissolution using USP Apparatus 1(baskets % 100 rpm) in 900 mL of simulated gastric fluid or 0.1N HCl (atpH 1.2).

In accordance with certain embodiments of the invention, thetaste-masked pharmaceutical composition is in the form of a tablet andexhibits low friability in order to be suitable for packaging blistersand bottles for storage, transportation and commercial distribution.Friability can be determined in accordance with the standardpharmaceutical test methods that are well known to those skilled in theart. Friability for tablets produced in accordance with certain aspectsof the invention will have a friability of not more than about 1% and inaccordance with certain embodiments not more than about 0.5%.

The following non-limiting examples illustrate the taste-maskedmicroparticle composition or an orally disintegrating tablet dosage formcomprising one or more therapeutic agent(s) requiring taste-masking,manufactured in accordance with the invention, which exhibits acceptabletaste-masking when placed in the mouth and substantially complete,rapid-release of the dose on entry into the stomach. All percentages andratios are by weight unless indicated otherwise.

Example 1

IR Beads (Drug Load: Approximately 16% Diphenhydramine Citrate):

Diphenhydramine citrate (293.4 g) was slowly added to an aqueoussolution of 32.6 g polyvinylpyrrolidone (binder) and 978 g of purifiedwater and mixed well. 60-80 mesh (177-250 micron) sugar spheres (1470 g)were coated with the drug-layering formulation in a Glatt fluid-bedcoater equipped with a bottom-spray Wurster insert. The drug containingpellets were dried, and a seal coat of Opadry Clear for a weight gain of2% was applied on the drug-layered beads.

Taste-Masked Beads (Drug Load: Approximately 12% Diphenhydramine Citrateat 25% Coating):

IR beads (1100 g) were coated with a solution ofEthocel/E100/plasticizer at a ratio of 46.3/46.3/7.4 dissolved in 98/2acetone/water for a weight gain of up to 25%. The plasticizer usedconsisted of Imwitor 900 (2.78%) and triethyl citrate (4.62%). Thecoated beads were dried in the Glatt GPCG-3. The actual assay values ofthe beads coated at 15 and 25% by weight were 0.073 and 0.064%,respectively. These taste-masked beads released 12% (15% coated) and 8%(25% coated) in 5 minutes when dissolution tested using the USPApparatus 2 (paddles @ 50 rpm in a phosphate buffer at pH 6.8).

Rapidly-Dispersing Microgranules:

The rapidly-dispersible microgranules comprising a sugar alcohol such asmannitol and a disintegrant such as crospovidone are prepared followingthe procedure disclosed in the co-pending U.S. patent application Ser.No. 10/827,106 filed Apr. 19, 2004. Currently, D-mannitol (147 kg) withan average particle size of approximately 20 μm or less (Pearlitol 25from Roquette, France) is blended with 8 kg of cross-linked povidone(Crospovidone XL-10 from ISP) in a high shear granulator (GMX 600 fromVector) and granulated with an aqueous solution of 5 kg mannitoldissolved in 37 kg purified water. Two such high shear granulationbatches are vacuum-transferred into a fluid-bed drier, Glatt GPCG 200through a Comil from Quadro and dried in the Glatt. Therapidly-dispersible microgranulcs thus obtained typically have anaverage particle size in the range of approximately 125-200 μm.

ODT Diphenhydramine Citrate:

Taste-masked beads at 15% and 25% coating and the mix (93.38%,rapidly-dispersing microgranulcs, 5.91% crospovidone, 0.35% orangeflavor, and 0.35% Aspartame) at a ratio of 1/3, were blended togetherand compressed into 441 mg (15% coating) or 500 mg (25% coating) tabletscontaining 20.3 mg of diphenhydramine citrate with an average hardnessof 6 kP. The tablets released 13% and 3% in about 5 minutes,respectively, when dissolution tested using the USP Apparatus 2 (paddles@ 50 rpm) at pH 6.8. In contrast, almost complete release of the activein about 5 minutes was observed when dissolution tested in 0.1N HCl asillustrated in FIG. 1.

Example 2 (Comparative)

Drug-Layered Diphenhydramine Hydrochloride Beads (Drug Load; 15%):

Diphenhydramine hydrochloride (375 g) was slowly added to an aqueoussolution of 41.8 g polyvinylpyrrolidone (binder) and 1667 g of purifiedwater and mixed well. 60-80 mesh sugar spheres (1470 g) were coated withthe drug-layering formulation in a Glatt GPCG 3. The drug containingpellets were dried, and a seal coat of Opadry Clear for a weight gain of4% was applied on the drug-layered beads.

Reference Example: Taste-Masked Beads with Ethylcellulose (EC-10) Alone

IR beads were coated with a solution of EC-10/Myvacet 9-45 at a ratio of90/10 dissolved in 95/5 acetone/water for a weight gain of up to 20%.The coated beads were dried in the Glatt GPCG-3. The taste-masked beadscoated at 20% typically release less than about 10% in 5 minutes whendissolution tested using the USP Apparatus 2 (paddles @ 50 rpm in aphosphate buffer at pH 6.8). The dissolution profiles in 0.1N HCl of thebeads with a membrane thickness of up to 20% by weight are shown in FIG.2 suggesting that both taste-masking and rapid release cannot beachieved when coated with ethylcellulose alone.

Example 3

Taste-Masked Beads with Ethylcellulose/Eudragit E100 (Drug Load:Approximately 12% Diphenhydramine Hydrochloride):

IR beads produced in Example 2 would be coated with a solution ofEC-10/E100 at a ratio of 46.3/46.3 with Myvacet 9-45/talc at 4.62/2.78dissolved in 95/5 acetone/water for a weight gain of up to 20%. Thecoated beads would be dried in the Glatt GPCG-3. The taste-masked beadscoated at 20% would release not more than about 15% in 5 minutes whendissolution tested using the USP Apparatus 2 (paddles @ 50 rpm in aphosphate buffer at pH 6.8). Yet the taste-masked beads would releasenot less than about 90% in 5 minutes when dissolution tested in 0.1NHCl, irrespective of the thickness of the membrane applied on the beads.

OPT Diphenhydramine Hydrochloride:

208 parts of taste-masked beads at 20% coating and 624 parts of the mix(93.38%, rapidly-dispersing microgranulcs, 5.91% crospovidone, 0.35%orange flavor, and 0.35% Aspartame) would be blended together andcompressed into 832 mg tablets containing 25 mg of diphenhydraminehydrochloride with an average hardness of 6 kP. The tablets wouldrelease not more than 10% in about 5 minutes when dissolution testedusing the USP Apparatus 2 (paddles % 50 rpm) at pH 6.8. In contrast,almost complete release of the active in about 20 minutes was observedwhen dissolution tested in 0.1N HCl.

Example 4 (Comparative) Reference Example: Taste-Masked Beads withPolyvinyl Acetate Alone (Drug Load: Approximately 12% DiphenhydramineHydrochloride)

IR beads produced in Example 2 were coated with a solution of polyvinylacetate (Kolloidon SR30D) with Myvacet 9-45/talc at 2.9/11.5 dissolvedin 87/13 ethanol/water for a weight gain of up to 20%. The coated beadswere dried in the Glatt GPCG-3. The taste-masked beads coated at 20%typically release less than 10% in 5 minutes when dissolution testedusing the USP Apparatus 2 (paddles % 50 rpm in a phosphate buffer at pH6.8). The dissolution profiles in 0.1N HCl of the beads with a membranethickness of up to 20% by weight are shown in FIG. 3. Based on theseobservations as well as the observations in Example 2, it is amply clearthat both effective taste-masking and rapid dissolution in acidicbuffers cannot be achieved when coated with a water-insoluble polymer(e.g., ethylcellulose or polyvinyl acetate) alone.

Example 5

Taste-Masked Beads with Polyvinyl Acetate/Eudragit E100 (Drug Load:Approximately 12% Diphenhydramine Hydrochloride):

IR beads produced in Example 2 would be coated with a solution ofpolyvinyl acetate/Eudragit E100 at a ratio of 65/25 with Myvacet9-45/talc at 6.5/3.5 dissolved in 90/10 ethanol/water for a weight gainof up to 20%. The coated beads would be dried in the Glatt GPCG-3. Thetaste-masked beads coated at 20% would release not more than 10% in 5minutes when dissolution tested using the USP Apparatus 2 (paddles @ 50rpm in a phosphate buffer at pH 6.8). Yet the taste-masked beads wouldrelease not less than 80% in 5 minutes when dissolution tested in 0.1NHCl, irrespective of the thickness of the membrane applied on the beads.

Example 6

Drug-Layered Cetirizine Dihydrochloride Beads (Drug Load: 8.4%):

Cetirizine dihydrochloride (180 g) was slowly added to an aqueoussolution of 15.7 g polyvinylpyrrolidone (binder) and 782.8 g of purifiedwater and mixed well. 60-80 mesh sugar spheres (1900 g) were coated withthe drug-layering formulation in a Glatt GPCG 3. The drug containingpellets were dried, and a seal coat of Opadry Clear for a weight gain of2% was applied on the drug-layered beads.

Taste-Masked Beads with Ethylcellulose/Eudragit E100:

IR beads were coated with a solution of EC-10/E100 at a ratio of46.3/46.3 with Myvacet 9-45/talc at a ratio of 4.62/2.78 dissolved in95/5 acetone/water for a weight gain of up to 20%. The coated beads weredried in the Glatt GPCG-3. The taste-masked beads coated at 20% released13% in 5 minutes when dissolution tested using the USP Apparatus 2(paddles @ 50 rpm in a phosphate buffer at pH 6.8). The dissolutionprofiles in 0.1N HCl of the beads with a membrane thickness of 5%, 10%,15% and 20% by weight are shown in FIG. 4.

ODT Cetirizine Dihydrochloride:

744 g of taste-masked beads at 20% coating, 1734 g of rapidly-dispersingmicrogranules, 110 g of crospovidone, 13 g orange flavor, and 13 g ofAspartame) would be blended together and compressed into 520 mg tabletscontaining 10 mg of cetirizine dihydrochloride with an average hardnessof 5 kP. The tablets would release not more than 10% in about 5 minuteswhen dissolution tested using the USP Apparatus 2 (paddles @ 50 rpm) atpH 6.8. In contrast, almost complete release of the active in about 20minutes was observed when dissolution tested in 0.1N HCl.

Example 7

Taste-Masked Microparticles of Sumatriptan Succinate (Drug Load:Approximately 63% of Sumatriptan Succinate):

Sumatriptan succinate (90%) was granulated with an aqueous solution (25%solids) of hydroxypropyl methylcellulose (Methocel K100LV at 10% byweight of the drug) in a high-shear granulator and tray-dried in aconvection oven. The resilient granules with an average particle size ofabout 200 μm would be coated with a 95/5 acetone/water solution (10%solids) containing 65/25 Ethocel (EC-10)/Eudragit E100 with TEC/talc ata ratio of 6.5/3.5 in a fluid-bed coater for a weight gain of up to 30%.The coated granules coated 30% would release less than 10% active in 5minutes at pH 6.8. Yet the taste-masked beads would release not lessthan 80% in 5 minutes when dissolution tested in 0.1N HCl, irrespectiveof the thickness of the membrane applied on the beads.

Sumatriptan Succinate ODT (100 mg of Sumatriptan):

The taste-masked microparticles (720 g), rapidly-dispersingmicrogranules (6,150 g) and an orange flavor (40 g), Aspartame (80 g),iron oxide (30 g) and crospovidone (200 g) would be blended together andcompressed into orally disintegrating tablets (average tablet weight ofapproximately 1 g and average hardness of 7.2 kP), using a rotary tabletpress equipped with an external lubricating system. SumatriptanSuccinate ODT (100 mg as sumatriptan) would disintegrate in less thanabout 60 seconds in the oral cavity exhibiting a pleasant taste. Thedrug-release would be not more than about 10% in 5 minutes in thesimulated saliva fluid (pH 6.8) and not less than about 85% in 30minutes in 0.1N HCl.

Changes may be made by persons skilled in the art in the constructionand the various components and assembly described herein or in the stepsor the sequence of steps of the method of manufacture described thereinwithout departing from the spirit and scope of the invention asdescribed herein:

What is claimed is:
 1. A pharmaceutical composition comprising: (1) aplurality of taste-masked particles, wherein each taste-masked particlecomprises: (a) a drug-containing core particle; and (b) a taste-maskingmembrane disposed on said drug-containing core particle comprising acombination of a water-insoluble polymer and a gastrosoluble polymer,wherein the water-insoluble polymer is selected from the groupconsisting of ethylcellulose, polyvinyl acetate, cellulose acetate,cellulose acetate phthalate, cellulose acetate butyrate, methacrylatecopolymers and combinations thereof, and the gastrosoluble polymer isselected from the group consisting of maltodextrin, aminoalkylmethacrylate copolymer, polyvinylacetate diethylaminoacetate, andcombinations thereof, wherein the ratio of the water-insoluble polymerto the gastrosoluble polymer is in the range of from about 95/5 to about50/50; and (2) a plurality of rapidly-dispersing microgranules having anaverage particle size of not more than about 400 μm comprising (i) adisintegrant and (ii) a sugar alcohol or a saccharide or a combinationthereof, wherein each of said disintegrant and sugar alcohol orsaccharide is present in the form of particles having an averageparticle diameter of not more than about 30 μm.
 2. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition releasesgreater than or equal to about 60% of the total amount of drug in 30minutes when tested for dissolution using United States PharmacopoeiaApparatus 2 using paddles at 50 rpm in 900 mL of pH 1.2 buffer.
 3. Thepharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition release not more than about 10% of the total amount of drugin about 3 minutes when dissolution tested in simulated saliva fluid atpH about 6.8.
 4. The pharmaceutical composition of claim 1, wherein theratio of said sugar alcohol, said saccharide or combination thereof tosaid disintegrant in the rapidly-dispersing microgranules is from about90/10 to about 99/1.
 5. The pharmaceutical composition of claim 1,comprising one or more drug(s) present in sufficient quantities to beadministered orally to a patient in need thereof at a prescribed dosingregimen to provide therapeutic efficacy.
 6. The pharmaceuticalcomposition of claim 1, wherein the drug-containing particle comprises adrug-layered bead comprising an inert particle coated with one or morepharmaceutically acceptable drug(s).
 7. The pharmaceutical compositionof claim 1, wherein the drug-containing particle comprises amicrogranule or an extruded and spheronized pellet, wherein themicrogranule or pellet comprise one or more pharmaceutically acceptabledrug(s) and (1) a polymeric binder, (2) a filler, and/or (3) diluents.8. The pharmaceutical composition of claim 1, wherein said drug requirestaste-masking.
 9. The pharmaceutical composition of claim 1, wherein thedrug is selected from the group consisting of diphenhydramine,ranitidine, cimetidine, famotidine, astemizole, cetirizine,fexofenadine, omeprazole, lansoprazole, sumatriptan, rezitriptan,eletriptan, zolmitriptan, ondansetron, granisetron, clonazepam,tiagabine, tizanidine, zolpidem, zaleplon, zafirlukast, montelukast,sildenafil, tadalafil, pharmaceutically acceptable salts thereof, andcombinations thereof.
 10. The pharmaceutical composition of claim 1,wherein the membrane thickness ranges from about 5% to 50% by weight ofthe coated particle.
 11. The pharmaceutical composition of claim 1,wherein the water-insoluble polymer comprises ethylcellulose and thegastrosoluble polymer comprises an aminoalkyl methacrylate copolymer.12. The pharmaceutical composition of claim 1, wherein the ratio ofrapidly-dispersing microgranules to taste-masked particles ranges fromabout 6/1 to about 2/1.
 13. The pharmaceutical composition of claim 1,wherein the rapidly-dispersing microgranules comprise a disintegrantselected from the group consisting of crosslinked polyvinylpyrrolidone,sodium starch glycolate, crosslinked sodium carboxymethylcellulose,low-substituted hydroxypropylcellulose and mixtures thereof.
 14. Thepharmaceutical composition of claim 1, wherein the average particle sizeof the drug-containing core particle is not more than about 400 μM. 15.The pharmaceutical composition of claim 1, wherein the rapidlydispersing microgranules comprise a sugar alcohol or a saccharideselected from the group consisting of mannitol, xylitol, sorbitol,maltol, maltitol, lactose, sucrose, maltose, and combinations thereof.16. The pharmaceutical composition of claim 1, wherein thepharmaceutical composition exhibits acceptable taste-masking when placedin the oral cavity for 60 seconds.
 17. The pharmaceutical composition ofclaim 1, wherein the rapidly dispersing microgranules have an averageparticle size of not more than 300 μm.
 18. The pharmaceuticalcomposition of claim 1, wherein the ratio of the water-insoluble polymerto the gastrosoluble polymer in the taste-masking membrane ranges fromabout 85/15 to about 65/35.
 19. A method of manufacturing apharmaceutical composition comprising: (a) preparing core particlescomprising a drug; and (b) coating the core particles by applying ataste-masking membrane comprising a mixture of water-insoluble polymerand a gastrosoluble polymer, wherein the water-insoluble polymer isselected from the group consisting of ethylcellulose, polyvinyl acetate,cellulose acetate, cellulose acetate phthalate, cellulose acetatebutyrate, methacrylate copolymers and combinations thereof, and thegastrosoluble polymer is selected from the group consisting ofmaltodextrin, aminoalkyl methacrylate copolymer, polyvinylacetatediethylaminoacetate, and combinations thereof, wherein the ratio of thewater-insoluble polymer to the gastrosoluble polymer in thetaste-masking membrane ranges from about 95/5 to about 50/50; (c)granulating particles of a sugar alcohol and/or a saccharide, eachparticle of sugar alcohol and/or saccharide having an average particlediameter of not more than 30 μm, with a disintegrant having an averageparticle diameter of not more than 30 μm to produce rapidly-dispersingmicrogranules with an average particle size of not more than about 400μm; (d) blending the taste-masking membrane coated microparticles ofstep (b) with the rapidly dispersing microgranules of step (c) at aratio of about 1/6 to about 1/2; and (e) compressing the blend of step(d) into orally disintegrating tablets.
 20. The method of claim 19,wherein the water-insoluble polymer comprises ethylcellulose and thegastrosoluble polymer comprises an aminoalkyl methacrylate copolymer.21. The method of claim 19, wherein said step of compressing (e)comprises utilizing a conventional rotary tablet press equipped with anexternal lubrication system to pre-lubricate the dies and punches. 22.The method of claim 19, wherein the orally disintegrating tablet, whentested for dissolution using United States Pharmacopoeia Apparatus 2using paddles at 50 rpm in 900 mL buffer, release not more than about10% of the total amount of the drug in about 3 minutes in a simulatedsaliva buffer at pH 6.8 and greater than or equal to about 60% of thetotal amount of the drug in about 30 minutes in an acidic buffer at pH1.2.
 23. The method of claim 19, wherein said rapidly-dispersingmicrogranules have an average particle size of not more than 300 μm. 24.The method of claim 19, wherein said orally disintegrating tablet has afriability of not more than about 1%.
 25. The method of claim 19,wherein the membrane is present in an amount of from about 5% to about50% based on the total weight of the coated particles.
 26. The method ofclaim 19, wherein the pharmaceutical composition releases not less thanabout 60% of the total amount of the drug in 30 minutes when tested fordissolution using United States Pharmacopeia Apparatus 2 using paddlesat 50 rpm in 900 mL of pH 1.2 buffer.
 27. The method of claim 19,wherein the ratio of the water-insoluble polymer to the gastrosolublepolymer in the taste-masking membrane ranges from about 85/15 to about65/35.